Halogenation Reactions of Alkyl Alcohols Employing Methyl Grignard Reagents

Grignard reagents are commonly used as carbanion equivalents. Herein, we report an example of Grignard reagents acting as halide nucleophiles to form alkyl iodides and bromides. We establish that Grignard reagents can convert alkyl mesylates into alkyl halides, as well as be employed in a one-pot halogenation reaction starting from alcohols, which proceed through mesylate intermediates. The halogenation reaction is confirmed to occur by an SN2 pathway with inversion of configuration and is demonstrated to be efficient on multi-gram scale.


■ INTRODUCTION
Since their discovery by Victor Grignard at the turn of the 20th century, alkylmagnesium halides have become ubiquitous organometallic reagents, typically serving as carbanion equivalents. 1,2 For example, Grignard reagents readily react with carbonyl moieties to afford secondary and tertiary alcohols (Scheme 1a). 3 Grignard reagents also participate in cross-coupling (XC) reactions, once again serving as carbanion equivalents (Scheme 1b). 4,5 Based on the structure of the Grignard reagent and the electronegativity difference of the Mg−X bond, it is plausible that Grignard reagents could also serve as halide nucleophiles. For example, subjecting epoxides to Grignard reagents can result in the formation of chlorohydrins. 6,7 Recently, in the context of development of a cross-electrophile coupling (XEC) reaction of mesylates, our laboratory has demonstrated that, in addition to the anticipated role of reducing the nickel catalyst, methylmagnesium iodide also serves as a nucleophilic iodide source (Scheme 1c). 8 Alkyl halides are versatile reagents in synthetic chemistry, most commonly employed in the alkylation of enolates and as starting materials for XC and XEC reactions, as well as the synthesis of Wittig and alkylmetal reagents. 9−13 Therefore, we sought to develop new halogenation reactions that start from alkyl alcohols. Numerous methods have been established to transform alcohols into alkyl halides, in general, by coupling alcohol activation with a nucleophilic halide source. 14, 15 For example, the Appel reaction, which converts alcohols to iodides with PPh 3 and I 2 , is a robust method employed by synthetic organic chemists. 16 In this manuscript, we report a halogenation reaction with methylmagnesium iodide and bromide for the rapid synthesis of alkyl iodides and bromides (Scheme 1d). These reactions showcase an unusual reactivity mode of Grignard reagents and are stereospecific and scalable.

■ RESULTS AND DISCUSSION
We began by optimizing the iodination reaction of alkyl mesylates utilizing mesylate 1 as a model substrate (Table 1).
This secondary mesylate was chosen due to the low volatility of the corresponding iodide, allowing for the ease of isolation and analysis of conversion. By performing the iodination reaction with MeMgI at room temperature for 1 h, 8 iodide 2 was observed in an 81% yield (entry 1). Excitingly, this reaction demonstrates minimal amounts of elimination products. In an effort to minimize the formation of alkenes, we performed the reaction at 0°C and observed decreased yields of alkenes 3 with no effect on the yield of iodide 2 (entry 2). In an attempt to further reduce the formation of the elimination products, the reaction temperature was lowered to −78°C. Although we observed a decreased formation of the elimination products, the conversion of mesylate 1 also decreased (entry 3). However, the yield of iodide 2 was not affected, which would prove useful for substrates with functional groups that are sensitive to Grignard reagents (vide infra). We hypothesized that at 0°C, shortening the reaction time to 5 min could potentially minimize the formation of elimination products while maintaining the high conversion of mesylate. We were pleased to see that this afforded iodide 2 in a 94% yield with a minimal amount of the elimination product 3 (entry 4). While freshly prepared MeMgI provided the highest rates, employing commercially available MeMgI also provided good results (entries 5 and 6).
We set out to distinguish whether the Grignard reagent itself, or MgI 2 , formed in situ via competitive Wurtz coupling during Grignard formation and the Schlenk equilibrium, serves as the iodide source for this reaction. 15,17,18 To investigate the source of iodide, we subjected mesylate 1 to reactions with MgI 2 . We observed a decrease in yield compared to the standard reaction conditions employing the Grignard reagent (c.f. entries 4 and 7). Because the Grignard reagent is prepared in Et 2 O, and the low solubility of MgI 2 in PhMe could account for the lower conversion of mesylate 1 to iodide 2 in entry 7, we performed the reaction with the addition of 30 μL of Et 2 O. 19 Addition of Et 2 O did indeed increase the yield of iodide 2 (entry 8); however, the rate remained significantly slower than when MeMeI was employed. At 0°C, the reaction with MgI 2 and Et 2 O only afforded the desired iodide 2 in a 6% yield, with 81% of mesylate 1 observed (entry 9); in comparison, at the same temperature and reaction times, reactions employing the commercial and freshly prepared Grignard reagent provided 75% and 92% yields, respectively (entries 4 and 5). These results are consistent with a faster iodination reaction when MeMgI is used. 20 We investigated if other Grignard reagents could be employed in the reaction to afford the alkyl iodide product from mesylate 1. Employing PhMgI instead of MeMgI resulted in a decrease in yield, with increased elimination and S N 2 substitution (entry 10).
With optimized reaction conditions in hand, we evaluated the functional group compatibility of the iodination reaction (Scheme 2a). Both secondary and primary alkyl mesylates provided the corresponding alkyl iodides 4−6 in excellent yields. As one would predict from an S N 2 mechanism, when a substrate bearing both an aryl mesylate and alkyl mesylate was subjected to the standard reaction conditions, iodination occurred at the alkyl mesylate to afford iodide 7. Next, we explored functional groups that are typically sensitive to nucleophilic Grignard reagents. Both a dibenzylated amine and an ester provided the desired iodides 8 and 9, respectively, when modified reaction conditions were utilized. Finally, the terpenol (R)-nopol cleanly underwent the iodination reaction to afford 10 in an 81% yield, comparing favorably to literature methods for the preparation of this compound. 21 Next, we envisioned a one-pot protocol where the alcohol could be directly transformed into the iodide by in situ mesylation followed by iodination with MeMgI (Scheme 2b). 22 A variety of secondary and primary alcohols underwent the one-pot reaction to give corresponding iodides in very good yields. We were pleased to observe that electron-donating groups (6, 11−12, 14−16), an electron-withdrawing group (13), and heteroaryl groups (17−18) were tolerated to provide the desired alkyl iodides in great yields. Excitingly, we observed that common protecting groups�silyl ether, benzyl ether, acetal, and carbamate �were also tolerated in the one-pot reaction (14, 19−21). We observed that 2-(4hydroxyphenyl) ethanol provided the phenol-substituted alkyl iodide 15 in an 85% yield, via mesylation, iodination, and in situ deprotection of the phenol. 23 Next, we investigated a benzylic alcohol substrate and observed the desired iodide 22 in moderate yields with a small amount of benzylic chloride as a byproduct. We anticipate that this benzylic chloride forms under the mesylation reaction conditions. 24 Tertiary alcohols proved difficult for this reaction, resulting in the formation of high yields of elimination products; however, under the onepot reaction conditions, iodide 23 could be obtained from 1adamantanol in a 59% yield with a minor amount of alkyl chloride. Another terpenol, citronellol, was subjected to the one-pot iodination reaction to yield iodide 24 in moderate yield. Additionally, we evaluated a series of substrates bearing functional groups that are known to be sensitive to Grignard reagents. For a substrate bearing a phthalimide, under the standard conditions at 0°C, the Grignard reagent reacted with both phthalimide and alkyl mesylate functionalities to afford 25. We were pleased to see that at −78°C, selectivity slightly favored the reaction of the alkyl mesylate to afford 26, which could be separated from undesired 25 and mesylate that were each observed in a <20% yield. Even more encouraging, an ester-containing substrate underwent the one-pot mesylation and iodination reaction at low temperature to provide 9 in a 73% yield. Finally, derivatives of lithocholic acid containing a secondary silyl ether, a secondary chloride, and a pendant ester all provided the desired product in good yields (27−29). In comparison to literature methods reported for the synthesis of the 23 known iodides in Scheme 2, the majority (15) of these reactions provided similar yields (within ∼10%) to those previously reported. Therefore, this reaction provides a new set of conditions for the formation of alkyl iodides, with the advantage that the reactions are rapid at low temperatures.
With the success of the iodination reaction, we aimed to synthesize alkyl bromides through similar two-step and onepot procedures (Scheme 3). 25 We were pleased to see that employing MeMgBr in place of MeMgI afforded the desired alkyl bromides. Both secondary and primary bromides with pendant aryl substituents (30−31, 33−34) were synthesized in great yields. Similar to the iodination reaction, silyl ether and acetal protecting groups were tolerated in the reaction (34− 35). An alkyl bromide (32) derived from chiral terpenol (R)nopol was obtained in a 75% yield. A lithocholic acid derivative with a secondary alkyl chloride was also well tolerated to afford 37 in this one-pot reaction. Finally, an ester-containing lithocholic acid derivative provided secondary bromide 38 in moderate yield.
Next, we turned our attention to the stereochemical outcome of the halogenation reaction. We hypothesized that a stereospecific S N 2 reaction was operative and would proceed cleanly with inversion. To confirm this hypothesis, we prepared enantioenriched alcohol 39 via a lipase-catalyzed kinetic resolution 26 and subjected it to the one-pot mesylation and iodination reaction (Scheme 4a). The reaction afforded enantioenriched alkyl iodide 5 in greater than 99% ee. To determine the stereochemical course of the reaction, we synthesized diastereomeric aryl-substituted 4-hydroxy tetrahydropyrans and investigated the outcome of the halogenation reaction. We subjected both cis-and trans-substituted tetrahydropyrans 40 to the bromination reaction (Scheme Scheme 2. Iodination Reaction of Mesylates and One-Pot Reaction of Alcohols to Form Alkyl Iodides a a 4b). We observed that cis-40 afforded trans-41, and similarly trans-40 provided cis-41, both in >20:1 dr. These results demonstrated that the halogenation reaction proceeds with inversion. These results also corroborated that the substitution occurs with high stereochemical fidelity. Finally, we investigated the scalability of the reaction (Scheme 4c). When we performed the one-pot mesylation and iodination reaction of (R)-nopol on a two-gram scale, the desired alkyl iodide 10 was afforded in a 92% yield. Therefore, this reaction provides a reliable method for the preparative-scale synthesis of alkyl iodides and bromides.

■ CONCLUSIONS
In summary, we have developed a halogenation reaction to transform alkyl alcohols into alkyl iodides and bromides that employs Grignard reagents as nucleophilic halide sources. The reaction is compatible with substrates containing various functional groups, including some that are typically sensitive to Grignard reagents. Through various stereochemical experiments, we have demonstrated that the halogenation reaction occurs through a stereospecific S N 2 reaction, proceeding with inversion. This reaction was also effective on the gram scale, which supports its synthetic utility. Most importantly, this work clearly establishes that methyl Grignard reagents can act as halide nucleophiles as well as carbanion equivalents. ■ EXPERIMENTAL SECTION General Procedures. All reactions were carried out under an atmosphere of N 2 when noted. All glassware was oven-or flame-dried prior to use. Tetrahydrofuran (THF), diethyl ether (Et 2 O), dichloromethane (DCM), dimethylformamide (DMF), and toluene (PhMe) were degassed with Ar and then passed through two 4 × 36 inch columns of anhydrous neutral A-2 alumina (8 × 14 mesh; LaRoche Chemicals; activated under a flow of argon at 350°C for 12 h) to remove H 2 O. 27 All other solvents utilized were purchased "anhydrous" commercially or purified as described. 1  , doublet of triplet of doublets (dtd), quartet of doublets (qd), triplet (t), doublet of triplets (dt), doublet of doublet of triplets (ddt), triplet of triplets (tt), quartet (q), triplet of quartets (tq), quintet (quint), sextet (sext), apparent singlet (as), apparent doublet (ad), apparent triplet (at), apparent quartet (aq), apparent quintet (aquint), apparent septet (asept), multiplet (m)], coupling constants [Hz], integration). Carbon chemical shifts are reported in ppm (δ) relative to TMS with the respective solvent resonance as the internal standard (CDCl 3 , δ 77.16 ppm). Fluorine chemical shifts are reported in ppm (δ) relative to the absolute frequency of 0.00 ppm in the proton spectrum. NMR data were collected at 25°C. Structural assignments were made with additional information from gCOSY experiments. Infrared (IR) spectra were obtained on a Thermo Scientific Nicolet iS5 spectrometer with an iD5 ATR tip (neat) and are reported in terms of the frequency of absorption (cm −1 ). Analytical thin-layer chromatography (TLC) was performed using Silica Gel 60 F254 precoated plates (0.25 mm thickness). Visualization was accomplished by irradiation with a UV lamp and/or staining with cerium ammonium molybdate (CAM), phosphomolybdic acid (PMA), or potassium permanganate (KMnO 4 ) solutions. Flash chromatography was performed using a SiliaFlash P60 (40−63 μm, 60 Å) from SiliCycle. Melting points (m.p.) were obtained using a MelTemp melting point apparatus and are uncorrected. Optical rotations were measured on a Rudolph Research Analytical Autopol III Automatic Polarimeter. SFC determinations of enantiopurity were determined by chiral SFC analysis and performed on Agilent Technologies HPLC (1260 series) system AD Chiralpak columns (100 bar, 50°C, 254 nm). High-resolution mass spectrometry was performed by the University of California, Irvine Mass Spectrometry Center.
Reagents. Methylmagnesium iodide was titrated with iodine prior to use. 28 All other chemicals were purchased commercially and used as received unless otherwise noted.
General Procedures for the Synthesis of Iodides and Bromides. Method A: Mesylation. A flame-dried round-bottom flask equipped with a stir bar was charged with alcohol (1.0 equiv) and DCM (0.20 M in alcohol) under N 2 . Et 3 N (1.5 equiv) and DMAP (0−0.2 equiv) were added, and the reaction mixture was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was added, and the reaction mixture was allowed to stir at rt for 1−16 h. Once complete by TLC, sat. NaHCO 3 (5 mL) was added, and the reaction mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo.
Preparation of MeMgI. Under a N 2 atmosphere, a three-neck round-bottom flask equipped with a stir bar, a reflux condenser, and a Schlenk filtration apparatus was charged with magnesium turnings (4.3 g, 180 mmol, 1.5 equiv). The flask and magnesium turnings were placed under vacuum and flame-dried and then back-filled with N 2 . A crystal of iodine (ca. 2 mg) was added to the flask, followed by anhydrous Et 2 O (30 mL). Freshly distilled iodomethane (7.5 mL, 120 mmol, 1.0 equiv) was added dropwise until the reaction initiated, and then the reaction mixture was cooled to 0°C and the remaining iodomethane was added slowly over 30 min to maintain a gentle reflux. The mixture was stirred for 2 h at rt and then filtered through the fritted Schlenk filter into a pear-shaped flask under a N 2 atmosphere. The pear-shaped flask was capped with a septum, sealed with parafilm, and stored either in the glovebox under a N 2 atmosphere for up to 8 weeks or in a −20°C freezer for up to 4 weeks. The resulting methyl Grignard reagent was typically between 2.9 and 3.1 M, as titrated by Knochel's method. 28 Method B: Iodination Reaction of Mesylates. Under a N 2 atmosphere, a flame-dried round-bottom flask equipped with a stir bar was charged with mesylate substrate (1.0 equiv) and PhMe (0.10 M in mesylate). The reaction mixture was cooled to 0°C, and then MeMgI (1.0 equiv, 2.4−3.2 M in Et 2 O) was added dropwise. The reaction mixture was allowed to stir for 5 min. If commercial MeMgI was employed, then the reaction mixture was allowed to stir for 1 h instead. The reaction mixture was warmed to rt for 5 min. MeOH was added dropwise to quench the reaction, and then the mixture was filtered through a plug of silica gel eluting with Et 2 O and concentrated in vacuo. The reaction mixture was purified by column chromatography. For the optimization reactions, phenyltrimethylsilane (PhTMS; 8.6 μL, 50 μmol) was added before purification and the yield was determined by 1 H NMR based on comparison to PhTMS as the internal standard.
Method C: One-Pot Reaction of Alcohols to Form Iodides. A flame-dried round-bottom flask equipped with a stir bar was charged with alcohol (1.0 equiv) and DCM (0.20 M in alcohol) under N 2 . Et 3 N (1.5 equiv) was added, and the reaction mixture was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was added, and the reaction mixture was allowed to stir at rt for 1 h. PhMe (0.20 M in alcohol) was added, the reaction mixture was cooled to 0°C, and then MeMgI (2.0 equiv, 2.4−3.2 M in Et 2 O) was added dropwise. The reaction mixture was allowed to stir at 0°C for 5 min. If commercial MeMgI was employed, the reaction mixture was allowed to stir for 1 h. Then, the reaction mixture was warmed to rt for 5 min. MeOH was added dropwise to quench the reaction, and then the mixture was filtered through a plug of silica gel eluting with Et 2 O and concentrated in vacuo. The reaction mixture was purified by column chromatography. If the reaction scale was 0.40 mmol or greater, then an extraction workup was carried out, instead of the silica gel plug, as follows. After warming up the reaction for 5 min, sat. aqueous NH 4 Cl was added dropwise. The layers were separated, and then the aqueous layer was extracted with DCM (×3). The organic layers were combined, dried over Na 2 SO 4 , and concentrated in vacuo. For the optimization reactions, phenyltrimethylsilane (PhTMS; 8.6 μL, 50. μmol) was added before purification and the yield was determined by 1 H NMR based on comparison to PhTMS as the internal standard.
Method D: Bromination Reaction of Mesylates. Under a N 2 atmosphere, a flame-dried round-bottom flask equipped with a stir bar was charged with mesylate substrate (1.0 equiv) and PhMe (0.10 M in mesylate). Then, commercial MeMgBr (2.0 equiv, 2.7−3.0 M in Et 2 O) was added dropwise, and the reaction mixture was allowed to stir at rt for 1 h. MeOH was added dropwise to quench the reaction, and then the mixture was filtered through a plug of silica gel eluting with Et 2 O and concentrated in vacuo. The reaction mixture was purified by column chromatography. For the optimization reactions, phenyltrimethylsilane (PhTMS; 8.6 μL, 50. μmol) was added before purification, and the yield was determined by 1 H NMR based on comparison to PhTMS as the internal standard.
Method E: One-Pot Reaction of Alcohols to Form Bromides. A flame-dried round-bottom flask equipped with a stir bar was charged with alcohol (1.0 equiv) and DCM (0.20 M in alcohol) under N 2 . Et 3 N (1.5 equiv) was added, and the reaction mixture was allowed to stir for 5 min. Then, MsCl (1.5 equiv) was added, and the reaction mixture was allowed to stir at rt for 1 h. PhMe (0.20 M in alcohol) was added, and then commercial MeMgBr (3.0 equiv, 2.7−3.0 M in Et 2 O) was added dropwise. The reaction mixture was allowed to stir for 1 h at rt. MeOH was added dropwise to quench the reaction, and then the mixture was filtered through a plug of silica gel eluting with Et 2 O and concentrated in vacuo. The reaction mixture was purified by column chromatography.
From Alcohol. Iodide 2 was prepared according to Method C. The following amounts of reagents were used: alcohol 42 (30. mg, 0.11 mmol, 1.0 equiv), MsCl (13 μL, 0.17 mmol, 1.5 equiv), Et 3 N (23 μL, 0.17 mmol, 1.5 equiv), DCM (0.55 mL, 0.20 M in substrate), MeMgI (76 μL, 0.22 mmol, 2.0 equiv, 2.9 M in Et 2 O), and PhMe (0.55 mL, 0.20 M in substrate). The residue was purified by column chromatography (0−5% EtOAc/hexanes) to afford the title compound as a yellow oil (38 mg, 0.10 mmol, 91% yield) containing alkene 3 (2 mg, 7 μmol, 6% yield). To remove the alkenes, a modified Sharpless asymmetric dihydroxylation was performed. 30 To a flamedried 20 mL vial was added AD-mix-β (0.15 g, 1.4 g/mmol). Then, t-BuOH (1.0 mL) and H 2 O (1.0 mL) were added via a syringe and the vial was capped. The vial was cooled to 0°C, and then the mixture of iodide 2 and alkenes 3 was added dropwise as a solution in t-BuOH (1.0 mL) and H 2 O (1.0 mL) via a syringe. The mixture was allowed to stir at 0°C for 24 h. To quench, Na 2 SO 3 (30. mg) was added and the mixture was allowed to warm to rt and stir for 30 min. Then, the mixture was transferred to a separatory funnel, and the organic layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (0−5% EtOAc/hexanes) to afford the title compound as a yellow oil (33 mg, 86 μmol, 78% yield over two steps). TLC R f = 0.4 (5% EtOAc/ hexanes, CAM stain); 1    . The residue was purified by column chromatography (0−5% EtOAc/hexanes) to afford the title compound as a pale-yellow oil (28 mg, 84 μmol, 84% yield) containing alkenes 3 (2.3 mg, 9.1 μmol, 9.0% yield). To remove the alkenes, a modified Sharpless asymmetric dihydroxylation was performed. 30 To a flame-dried 20 mL vial was added AD-mix-β (0.14 g, 1.4 g/mmol). Then, t-BuOH (1.0 mL) and H 2 O (1.0 mL) were added via a syringe and the vial was capped. The vial was cooled to 0°C , and then the mixture of bromide 30 and alkenes 3 was added dropwise as a solution in t-BuOH (1.0 mL) and H 2 O (1.0 mL) via a syringe. The mixture was allowed to stir at 0°C for 24 h. To quench, Na 2 SO 3 (30. mg) was added and the mixture was allowed to warm to rt and stir for 30 min. Then, the mixture was transferred to a separatory funnel, and the organic layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography (0−5% EtOAc/hexanes) to afford the title compound as a yellow oil (29 mg, 87 μmol, 87% yield over two steps). TLC R f = 0.   33 From Alcohol. Iodide 4 was prepared according to a modified Method C. The following amounts of reagents were used: alcohol 43 . Upon the addition of MeMgI, the reaction mixture was allowed to stir at 0°C for 1 h. The residue was purified by flash column chromatography (0−10% Et 2 O/hexanes) to afford the title compound as a colorless oil (29 mg, 0.11 mmol, 91%). Refer to iodide 4 above for analytical data.
Alcohol 39 was prepared according to the following procedure. A flame-dried round-bottom flask with a stir bar was charged with aldehyde SI-4 (0.78 g, 4.4 mmol, 1.0 equiv) and anhydrous THF (25 mL, 0.20 M in substrate) and cooled to 0°C. Then, MeMgCl (2.2 mL, 6.6 mmol, 1.5 equiv) was added dropwise. The reaction mixture was allowed to stir at rt overnight. The reaction was quenched with sat. aqueous NH 4 Cl (10 mL), and the mixture was extracted with Et 2 O (3 ×20 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography (0−30% EtOAc/hexanes) to afford the title compound as a pale-yellow oil (0.   . Upon the addition of MsCl, the reaction mixture was allowed to stir at rt for 5 min. The residue was purified by column chromatography (0−5% EtOAc/hexanes) to afford the title compound as a yellow oil (31 mg, 87 μmol, 87% yield). Refer to iodide 6 above for analytical data.
From Alcohol Using Commercially Available MeMgI. Iodide 6 was prepared according to a modified Method C. The following amounts of reagents were used: alcohol 46 (24 mg, 0. . Commercial MeMgI was used. Upon the addition of MeMgI, the reaction mixture was allowed to stir at 0°C for 1 h. The residue was purified by column chromatography (0−5% EtOAc/ hexanes) to afford the title compound as a yellow oil (31 mg, 88 μmol, 88% yield). Refer to iodide 6 above for analytical data. in substrate). The reaction mixture was allowed to stir for 5 min at rt. Benzyl bromide (0.75 mL, 6.3 mmol, 2.1 equiv) was then added dropwise via a syringe, and the reaction mixture was allowed to stir for 16 h at rt. The reaction was filtered over a pad of celite while flushing with DCM and then concentrated in vacuo. The residue was purified by flash column chromatography (0−30% EtOAc/hexanes) to afford the title compound as a yellow oil (0.60 g, 2.4 mmol, 79%). TLC R f = 0.3 (20% EtOAc/hexanes); 1  Upon addition of MeMgI, the reaction mixture was allowed to stir at −78°C for 3 h. The residue was purified by flash column chromatography (0−10% Et 2 O/hexanes) to afford the title compound as a pale-yellow oil (24 mg, 90. μmol, 73%). Refer to iodide 9 above for analytical data. . The residue was purified by flash column chromatography (100% hexanes) to afford the title compound as a colorless oil (25 mg, 91 μmol, 91%). Refer to iodide 10 above for analytical data.
From Alcohol, 12 mmol Scale. To a flame-dried round-bottom flask equipped with a stir bar was added (1R)-(−)-nopol (2.1 mL, 12 mmol, 1.0 equiv), anhydrous DCM (60. mL, 0.20 M in substrate), then Et 3 N (2.5 mL, 18 mmol, 1.5 equiv). The reaction mixture was allowed to stir at rt for 5 min before adding MsCl (1.4 mL, 18 mmol, 1.5 equiv). The reaction mixture was allowed to stir at rt for 1 h before adding PhMe (60. mL, 0.20 M in substrate) and cooling to 0°C . After 5 min at 0°C, commercial MeMgI (15 mL, 36 mmol, 2.4 M in Et 2 O) was added, and the reaction mixture was allowed to stir at 0°C for 5 min. To quench, sat. NH 4 Cl solution was added, and the biphasic mixture was extracted with DCM (×3), washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography (100% hexanes) to afford the title compound as a colorless oil (3.1 g, 11 mmol, 92% yield). Refer to iodide 10 above for analytical data. Refer to bromide 32 above for analytical data.
Alcohol 53 was prepared according to a modified procedure reported by Cole. 43 Under a N 2 atmosphere, a flame-dried roundbottom flask equipped with a stir bar was charged with the 3-(4bromophenyl)propionic acid (1.1 g, 5.0 mmol, 1.0 equiv) and THF (10. mL, 0.50 M in substrate). The reaction mixture was cooled to 0°C and BH 3 ·THF (15 mL, 1.5 mmol, 3.0 equiv, 1.0 M in THF) was added dropwise. The mixture was brought to rt and allowed to stir for 16 h. Then, glacial acetic acid was added dropwise until quenched, followed by the addition of sat. aqueous NaHCO 3 until a pH of 7 was achieved. This mixture was extracted with EtOAc (×3), and the organic layers were combined, dried with Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (0− 20% EtOAc/hexanes) to afford the title compound as a yellow oil  Alcohol 55 was prepared according to the following procedure. In a glovebox, a flame-dried round-bottom flask with a stir bar was charged with LiAlH 4 (88 mg, 2.3 mmol, 2.2 equiv), capped, and brought out of the glovebox. A N 2 inlet and THF (5.3 mL, 0.20 M in substrate) was added. The mixture was cooled to 0°C, and carboxylic acid SI-6 (0.29 g, 1.1 mmol, 1.0 equiv) was added as a solution in THF (1.0 M in substrate). The reaction mixture was warmed to rt and allowed to stir overnight. Then, sat. aqueous NH 4 Cl was added, and the crude mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (0−25% EtOAc/hexanes) to afford the title compound as a colorless oil (0.14 g, 0.51 mmol, 49% yield). TLC  . Mesylation was allowed to stir for 5 min. Upon addition of MeMgI, the reaction mixture was stirred at 0°C for 5 mins, then the flask was warmed up to rt and MeMgCl (33 μL, 0.10 mmol, 1.0 equiv) was added dropwise. In the development of this reaction, we observed that subjecting an alkyl mesylate to MeMgCl resulted in conversion back to the alcohol instead of to the alkyl chloride, so to obtain the phenol as the exclusive product, we carried out this subsequent step. The reaction mixture was stirred for 1 h at rt, quenched with MeOH, filtered through a pad of silica gel eluting with 100% Et 2 O, and concentrated in vacuo. The residue was purified by column chromatography ( Alcohol 56 was prepared according to a modified procedure reported by Cole. 43 Under a N 2 atmosphere, a flame-dried roundbottom flask equipped with a stir bar was charged with 2-(4methoxyphenyl) acetic acid (2.5 g, 15 mmol, 1.0 equiv) and THF (30. mL, 0.50 M in substrate). The reaction mixture was cooled to 0°C and BH 3 ·THF (45 mL, 45 mmol, 3.0 equiv, 1.0 M in THF) was added dropwise. The mixture was brought to rt and allowed to stir for 16 h. Then, glacial acetic acid was added dropwise until quenched, followed by the addition of sat. aqueous NaHCO 3 until a pH of 7 was achieved. This mixture was extracted with EtOAc (×3), and the organic layers were combined, dried with Na 2 SO 4 , and concentrated in vacuo. The residue was purified by column chromatography (0− 50% EtOAc/hexanes) to afford the title compound as a colorless oil (2.3 g, 15 2 mg, 2 μmol, 2%). To remove the alkenes, a modified Sharpless asymmetric dihydroxylation was performed. 30 To a flame-dried 20 mL vial was added AD-mix-β (0.14 g, 1.4 g/mmol). Then t-BuOH (1.0 mL) and H 2 O (1.0 mL) were added via syringe and the vial was capped. The vial was cooled to 0°C and then the mixture of iodide 17 and alkenes 57 was added dropwise as a solution in t-BuOH (1.0 mL) and H 2 O (1.0 mL) via syringe. The mixture was allowed to stir at 0°C for 24 h. To quench, Na 2 SO 3 (30. mg) was added and the mixture was allowed to warm to rt and stir for 30 min. Then the mixture was transferred to a separatory funnel, and the organic layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo. The residue was purified by column chromatography ( Alcohol 58 was prepared according to a modified procedure reported by Cole. 43 Under a N 2 atmosphere, a flame-dried roundbottom flask equipped with a stir bar was charged with indomethacin (0.36 g, 1.0 mmol, 1.0 equiv) and THF (2.0 mL, 0.50 M in substrate). The reaction mixture was cooled to 0°C and BH 3 ·THF (3.0 mL, 3.0 mmol, 3.0 equiv) was added dropwise. The mixture was brought to rt and allowed to stir for 16 h. Then, glacial acetic acid was added dropwise until quenched, followed by the addition of sat. aqueous NaHCO 3 until a pH of 7 was achieved. This mixture was extracted with EtOAc (×3), and the organic layers were combined, dried with Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography (0−30% EtOAc/hexanes) to afford the title compound as a brown oil (23 mg, 0.11 mmol, 11%). TLC R f = 0.2 (50% EtOAc/hexanes); 1   Alcohol 59 was prepared according to the following procedure. Open to air, a round-bottom flask with a stir bar was charged with benzyloxyacetaldehyde (0.70 mL, 5.0 mmol, 1.0 equiv), NaBH 4 (0.38 g, 10. mmol, 2.0 equiv), and MeOH (25 mL, 0.20 M in substrate). The reaction mixture was stirred for 30 min. After completion, the reaction mixture was concentrated in vacuo, and then dissolved in DCM. H 2 O was added and the aqueous layer was extracted with DCM. The combined organic layers were dried and concentrated in vacuo. The residue was purified by flash column chromatography (0− 50% EtOAc/hexanes) to afford the title compound as a pale-yellow oil Alcohol 60 was prepared according to a procedure reported by Molander. 58 To a flame-dried round-bottom flask equipped with a stir bar was added 3-hydroxypropyltriphenylphosphonium bromide (0.48 g, 1.2 mmol, 1.2 equiv), then THF (5.0 mL, 0.20 M in substrate). The reaction mixture was cooled to 0°C before adding n-BuLi (1.3 mL, 3.2 mmol, 3.2 equiv, 2.5 M in hexanes). The reaction mixture was allowed to stir at 0°C for 30 min. Then, 2,3-isopropylideneglyceraldehyde (260 mg, 1.0 mmol, 1.0 equiv, 50% w/w in DCM) was added dropwise via a syringe, and the reaction mixture was allowed to stir at 0°C rt for 16 h. To quench, sat. NH 4 Cl solution was added. The reaction mixture was extracted with EtOAc (3 ×10 mL), and the combined organic layers were washed with brine, dried over Na 2 SO 4 , and concentrated in vacuo. The residue was purified by flash column chromatography (0−30% EtOAc/hexanes) to afford the title compound as a mixture of diastereomers as a yellow oil (0.12 g, 0.71 mmol, 71%, 1.6:1 dr). TLC R f = 0.2 (50% EtOAc/hexanes, KMnO 4 stain) For clarity, the 1 H NMR data of the major and minor diastereomers have been tabulated separately. Analytical data is consistent with literature values. 58 Major Diastereomer. 1